Successful weed management particularly use of chemical control is very important for commercial lettuce production on organic soils in the Everglades Agricultural Area in south Florida. Field experiments were conducted in 2016 and 2017 to determine the efficacy of PRE herbicides (pronamide, bensulide, imazethapyr, or oxyfluorfen) applied alone or followed by POST application of imazethapyr for weed control and lettuce (romaine and iceberg) yield. Preemergence oxyfluorfen (0.56 kg ha−1) resulted in significant lettuce injury, including stand loss, while PRE applications of pronamide (4.44 kg ha−1), bensulide (5.6 and 10.1 kg ha−1), or imazethapyr (0.035 g ha−1) resulted in transient lettuce injury and no significant stand loss. Similarly, PRE pronamide, bensulide, and imazethapyr followed by POST imazethapyr did not result in significant lettuce stand loss or injury. When contrasted as a group, PRE herbicides followed by POST imazethapyr provided better spiny amaranth and common lambsquarters control compared to PRE herbicides or POST imazethapyr only treatments. Lettuce yield was highest in PRE herbicides followed by POST imazethapyr compared to PRE herbicides or POST imazethapyr only treatments, indicating a yield benefit of having a PRE followed by POST herbicide weed control program in lettuce grown on organic soils. However, oxyfluorfen is not an option for lettuce on organic soils because of unacceptable stand reduction and crop injury. The choice of PRE pronamide, bensulide, or imazethapyr followed by POST imazethapyr program for broadleaf weed control in lettuce on organic soils will depend on the species present, cost and ease of application.